Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones.
An important class of cellular proteins, which includes members of the p21ras family, undergoes posttranslational farnesylation, a modification required for their partition to membranes. Specific farnesyl transferase inhibitors (FTIs) have been developed that selectively inhibit the processing of these proteins. FTIs have been shown to be potent inhibitors of tumor cell growth in cell culture and in murine models and at doses that cause little toxicity to the animal. These data suggest that these drugs might be useful therapeutic agents. We now report that, when FTI is combined with some cytotoxic antineoplastic drugs, the effects on tumor cells are additive. No interference is noted. Furthermore, FTI and agents that prevent microtubule depolymerization, such as taxol or epothilones, act synergistically to inhibit cell growth. FTI causes increased sensitivity to induction of metaphase block by these agents, suggesting that a farnesylated protein may regulate the mitotic check point. The findings imply that FTI may be a useful agent for the treatment of tumors with wild-type ras that are sensitive to taxanes.
Moasser
M M
MM
Department of Medicine, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Sepp-Lorenzino
L
L
Kohl
N E
NE
Oliff
A
A
Balog
A
A
Su
D S
DS
Danishefsky
S J
SJ
Rosen
N
N
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D034261:Epothilones; D051231:Farnesyltranstransferase; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D034261:Epothilones; C096898:L 744832; D013844:Thiazoles; C110841:desoxyepothilone A; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D017239:Paclitaxel